The Philadelphia-chromosome negative myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders, which include Polycythemia Vera (PV), Essential Thrombocytosis (ET), and Primary Myelofibrosis (PMF)). MPNs carry a risk of morbidity and mortality. Importantly, however, a substantial proportion of patients with PV, ET or PMF develop transformation to acute myeloid leukemia (AML). This progression is often fatal, with a median survival of less than four months. Standard treatments available for AML have proven to have little or no impact on outcome in these patients. Thus, there is a pressing need to develop new treatments. Using target gene analysis, we have begun genomic assessment of post- MPN AML. Our preliminary data demonstrates that the mutations found at the time of leukemic transformation (LT) differs from those commonly found in de novo AML. This data suggests that post-MPN AML is genetically distinct from de novo AML, and that more expansive efforts are required to further define the spectrum of mutations in post-MPN AML. We have developed the first reported genetically accurate murine model of post-MPN AML. We have performed detailed analysis of this initial model. Further, using this model, we have begun testing new therapeutic strategies in vivo and in vitro. We seek to further understand the genetic events that are involved in the progression of MPN to AML. This information will then be used to develop new genetically accurate pre-clinical models of progression to AML. We then plan to use these models to test new therapeutic strategies. Using the genetic and biological insights we will gain from these efforts, we seek to ultimately translate these findings into new therapeutic strategies for this devastating disease. The studies will be led by Dr. Raajit Rampal, a junior faculty member at Memorial Sloan-Kettering Cancer Center under the mentorship of Dr. Ross Levine. Dr. Levine is a leader in leukemia research with an established track record of effectively, rapidly mentoring former trainees into independence. The Memorial Sloan-Kettering Cancer Center, and the Human Oncology and Pathogenesis program, led by Dr. Charles Sawyers, offers an exceptional environment for cultivating a developing career in translational cancer research. To achieve his long-term goal of becoming an independent investigator Dr. Rampal has developed a structured curriculum of activities aimed at broadening her knowledge base, expanding technical repertoire and developing leadership skills, and has assembled an advisory committee of leading scientists.